ABSTRACT I am seeking to facilitate my transition to an independent researcher through this K99/R00 funding mechanism by studying the role of alcohol in the pathology of asthma. Asthma is one of the most common chronic diseases in developed countries. Currently there are more than 300 million people worldwide with asthma and it is estimated that by 2025 over 400 million people will be diagnosed with asthma. It is an episodic airway disease characterized by airway hyperresponsiveness (AHR), reversible airway obstruction, chronic airway inflammation, and mucus hypersecretion. Presently there is no cure for asthma only symptomatic treatment. Alcohol is one of the most used and abused drugs in the world with more than 17 million alcoholics in the United States alone. With the rapidly growing number of people who consume alcohol on a regular basis (66%) there is a coinciding increase in the number of people seeking medical attention for alcohol-induced problems. While heavy alcohol intake clearly damages the brain and liver, the lung is also a target for the toxic effects of alcohol. Historical accounts of alcohol administration to patients with breathing problems suggest that alcohol may have bronchodilating properties. From these historical accounts and previous work published from our laboratory demonstrating roles for cAMP, cGMP, and nitric oxide, all modulators of airway function, we hypothesize that: Alcohol reduces airway hyperresponsiveness (AHR) and airway inflammation in asthma. In this proposal we will answer the following questions: 1) To what extent will alcohol attenuate AHR and inflammation in allergic asthma? 2) By what mechanism(s) is this occurring? These questions will be answered through the following specific aims: 1) Characterize the effect of alcohol exposure on allergen induced AHR and airway inflammation; 2) Determine mechanism(s) of alcohol's effects on allergic asthma; and 3) Establish the impact of alcohol on airway function human subjects with mild persistent asthma. The training plan presented in this proposal will facilitate a seamless transition to an independent research career. Furthermore, the proposed experimental design will lead to a greater understanding of how alcohol modifies the pathology of asthma and may lead to better management and treatment of this disease. The candidate's proposed career development plan includes training in advanced animal protocols and clinical concepts in pulmonary medicine. To ensure that the candidate accomplishes his research and training goals, he will have an excellent mentor and advisors, rich academic surroundings, and strong institutional commitment.